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Gene Scoring Criteria v3.0

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Category S (Syndromic)

Mutations are associated with a substantial degree of increased risk and are consistently associated with additional features not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as #S (e.g. 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as ‘S’

Category 1 (High confidence)

1.1 Recurrent and convincing mutations accompanied by a rigorous statistical comparison with the mutation frequency in controls, and independent replication. Full sequencing of a comparable number of cases and controls is required. Convincing is defined as ‘likely to be functional’, or showing perfect segregation of mutations and phenotype in a large pedigree.

1.2 For results from association studies, those that reach genome-wide significance, uniquely implicating a single gene, and are independently replicated or reach genome-wide significance via meta-analysis of all current association studies. For genome-wide significant variants in an intergenic region, a nearby flanking gene would be included if it’s the only gene in strong LD with the intergenic variant, or if the variant if also associated with altered expression of a particular flanking gene (or another line of strong evidence implicating this gene).

Category 2 (Strong candidate)

2.1 Rare mutations that are recurrent and convincing accompanied by a rigorous statistical comparison with the mutation frequency in controls. Independent replication is not required. Full sequencing of a comparable number of cases and controls is required. Convincing is defined as ‘likely to be functional’, or showing perfect segregation of mutations and phenotype in a large pedigree. Rare de novo variants, likely to be disruptive, in three or more unrelated cases would qualify here.

2.2 For results from association studies, those that reach genome-wide significance, uniquely implicating a single gene, but with no independent replication. For genome-wide significant variants in an intergenic region, a nearby flanking gene would be included if it’s the only gene in strong LD with the intergenic variant, or if the variant is also associated with altered expression of a particular flanking gene (or another line of strong evidence implicating this gene).

2.3 Consistently replicated association of the same allele, falling short of genome wide significance, but is accompanied by evidence that the risk variant has a relevant functional effect in humans. ‘Consistently replicated’ means replication of the same variant in each follow-up association study that is appropriately powered and involves a population of the same ancestry, or inconsistent but overall significant by meta-analysis. In this regard, ‘gene-based’ tests of association are acceptable as evidence of an association if performed in the original study, but would not be considered as evidence simply to ‘rescue’ a subsequent study that finds a variant association that is different from the associated variant in the original study.

Category 3 (Suggestive evidence)

3.1 Genes that meet at least two of criteria 4.1, 4.2, and 4.3, or meet one of those criteria and at least one line of category 4 accessory evidence.

3.2 Genes that meet category 2.3 criteria, but without accompanying functional evidence.

3.3 Rare de novo variants, likely to be disruptive, in two or more unrelated cases.

Category 4 (Minimal evidence)

4.1 Any gene in an ASD-associated multi-genic CNV (including syndromic) for which there is no other independent evidence.

4.2 Genes proximal to genome-wide significant intergenic variants that don’t meet category 1 or 2 criteria.

4.3 Any significant, convincing, but unreplicated association study. Also, multiple but inconsistent reports of association that is not overall significant by meta-analysis.

4.4 Genes with a series of two or more putative mutations identified (e.g. non-synonymous substitutions, single-gene deletion, duplication, disruption by translocation) for which there is not rigorous statistical comparison with controls.

4.5 A single rare de novo variant, likely to be disruptive.

Accessory evidence to raise a gene from category 4 to category 3:

• Altered expression or function in ASD cases vs. controls in any tissue, whether as a function of genotype or not.
• Strong evidence for involvement in a related phenotype or disorder (specifically including ADHD, ASD-related endophenotypes (e.g. language impairment), bipolar disorder, epilepsy, intellectual disability, schizophrenia.
• Genes shown to be associated with ASD risk via genetic epistasis with another gene.

Category 5 (Hypothesized but untested)

5.1 Genes for which the only evidence comes from studies of model organisms, without statistical/genetic support in human studies.

5.2 Genes in a region of linkage with no unique evidence for that gene vs. others nearby.

5.3 Genes shown to functionally interact with category 1-3 ASD candidate genes.

5.4 Genes with a single rare variant observed in a single ASD case/family.

Category 6 (Evidence does not support a role in ASD)

6.1 The weight of the evidence argues against a role in autism.

Last updated 07 Oct 2013